Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant Streptococcus pneumoniae pneumonia

Trovafloxacin is a potentially useful agent for treatment of infections caused by cephalosporin-resistant Streptococcus pneumoniae. We studied the effectiveness of trovafloxacin therapy and examined the correlation between pharmacodynamic indices in serum and lung, and bacterial killing. Immunocompetent Balb/c mice were infected by intranasal inoculation of a cephalosporin-resistant S. pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 and 0.06 mg/L, respectively). Trovafloxacin 10-30 mg/kg/day in one or three divided doses was started 15 h after infection. Serum and lung drug concentrations were measured at multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung concentrations approximately 30 min later. The serum T(1/2) was approximately 9 h and lung T(1/2) varied from 5 to 9 h. Lung AUC and C(max) values were 2-3 times greater than those in serum. At the start of therapy lung bacterial concentrations were 8.4 ± 0.3 log₁₀ cfu/mL and 24 h later had decreased by 3.5 ± 0.2, 4.0 ± 0.2, 0.8 ± 0.3 and 1.0 ± 1.2 log₁₀ cfu/mL with 30 mg/kg x 1, 10 mg/kg x 3, 10 mg/kg x 1 and 3.3 mg/kg x 3 regimens, respectively. Although the larger dosages were more effective (P < 0.001) the differences between divided and single dosage regimens were not significant. Trovafloxacin serum AUC/MIC ratio correlated best with bacterial killing in the lungs over 24 h. Trovafloxacin is likely to be useful in the treatment of cephalosporin-resistant S. pneumoniae pneumonia.